Epigenetic modifications precede molecular alterations and drive human hepatocarcinogenesis

Area of Science:

• Oncology
• Epigenetics
• Genomics

Background:

• Primary liver cancer development is a complex, multistage process.
• A comprehensive understanding of sequential epigenetic alterations in hepatocarcinogenesis is lacking.

Purpose of the Study:

• To perform genome-wide methylome and transcriptome profiling of liver tissues at various stages of hepatocellular carcinoma (HCC) development.
• To identify and validate epigenetic drivers of HCC and explore their therapeutic potential.

Main Methods:

• Infinium Human Methylation 450k BeadChips and RNA-Seq for methylome and transcriptome profiling.
• Integrative genomic analyses, mitochondrial DNA sequencing, and validation in independent cohorts (n=887).
• Functional studies involving Striatin 4 (STRN4) inhibition in HCC cell lines.

Main Results:

• DNA methylation alterations progressively increased from liver cirrhosis to dysplastic lesions and early HCC.
• Early epigenetic changes impacted apoptosis, immune regulation, and stemness pathways; late changes affected cell survival, proliferation, and invasion.
• Identified 23 putative epidrivers with prognostic value, including epigenetically regulated STRN4, whose inhibition suppressed HCC tumorigenicity.

Conclusions:

• Integrative genomic analyses define critical epigenetic driver alterations in HCC development.
• STRN4 is a potential therapeutic target for hepatocellular carcinoma.
• The study provides insights into the multistage epigenetic landscape of liver cancer.